Sustained delivery of therapeutic agents to an eye compartment

ABSTRACT

Compositions and methods for treating eye disorders by administering a drug delivery system into an eye compartment of the patient, wherein the drug delivery system contains a particle containing a core; a coating associated with the particle, wherein the coating is covalently or non-covalently associated with the particle and presents a hydrophilic region to the environment around the particle; and a therapeutic agent are disclosed. The eye compartment can exhibit reduced inflammation or IOP after administration of the drug delivery systems to a patient than if a drug delivery system including an uncoated particle were administered to the patient.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/138,132, filed Apr. 25, 2016, entitled “Sustained Delivery ofTherapeutic Agents to an Eye Compartment”, by Peter J. McDonnell, YasinA. Khan, Samuel K. Lai, Renata T. Kashiwabuchi, Ashley Behrens, andJustin S. Hanes, which is a continuation of U.S. application Ser. No.14/521,904, filed Oct. 23, 2014, now U.S. Pat. No. 9,566,242, issuedFeb. 14, 2017, U.S. application Ser. No. 13/581,454, filed on Aug. 27,2012, now U.S. Pat. No. 8,889,193, issued Nov. 18, 2014, which is aNational Stage of International Application No. PCT/US2011/026321 filedwith the Patent Cooperation Treaty on Feb. 25, 2011, which claimspriority to and benefit of U.S. Provisional Applications Nos.61/308,053, 61/308,042, and 61/308,035, all filed on Feb. 25, 2010, thecontents of each being hereby incorporated by reference in theirentirety.

TECHNICAL FIELD

The compositions and methods disclosed herein can be used for treatingeye disorders, for example by administering a drug delivery system intoan eye compartment of a patient.

BACKGROUND

Treatment of eye disorders can pose significant problems. For example,the management of many corneal diseases requires that therapeuticagents, such as drugs or other medication, remain at therapeutic levelsin the corneal tissue for extended periods of time. Topical drops remainthe most common route of drug administration to the eye, especially thecornea. Certain patients, however, including those patients havingfungal and/or amoebic infections of the cornea, as well as cornealtransplant recipients, require therapeutic doses of medications to becontinuously maintained in the corneal tissues. To achieve suchtherapeutic doses of a particular medication in corneal tissues, suchpatients are required to endure lengthy and arduous dosing regimens thatoften involve topically instilling medications hourly.

The efficacy of topical dosing can be diminished by poor patientcompliance. The repeated administration of one or more medications canalso lead to toxicity, which can be related to excess dosing of themedications and/or their preservative agents. Injections offree-standing mediations into the corneal stroma also have been employedin certain situations. This approach, however, fails to result insustained presence of medications within the therapeutic window due torapid diffusion of the medication out of the cornea. The combination ofpoor compliance and poor penetration of topically-administeredmedications into the corneal stroma can result in treatment failure,even when the pathogenic organism or other cause of disease is known tobe “sensitive” to the therapy or should otherwise respond to themedication being applied to the eye.

Such treatment difficulties are not only observed with corneal diseases.Disorders common to the anterior chamber (AC) can also pose problems.For example, cataract extraction is one of the most commonly performedsurgical procedures in the United States. Both the incidence ofcataracts and the frequency of their extraction surgeries continue torise. Anti-inflammatory agents and antimicrobials both are requiredduring the post-operative period and typically must be administered formany weeks. Unfortunately, the poor ocular bioavailability of thesedrugs often necessitates complicated and arduous dosing regimens thatcan lead to poor patient compliance, which, in turn, ultimatelycontributes to poor surgical outcomes and other complications. Currentstate-of-the art treatment involves sustained delivery systems that areinjected into the subconjunctival space at the end of surgery. However,such sustained release drug systems afford limited intraocularbioavailability of delivered medications due to barriers to drugpenetration. Further, medications delivered to an extraocular site, evenin a sustained manner, will have lower intraocular bioavailability dueto barriers that prevent penetration.

Injecting medications directly into the AC of the eye at the end ofsurgery has been an alternative to topical treatment. Free-standingmedications injected into the AC, however, are readily eliminated duringaqueous humor clearance. As a result, the retention of medicationsinjected into the AC is short and their bioavailability fails to meetclinical guidelines.

The delivery of medications to the posterior segment of the eye has alsobeen a challenge for ophthalmologists. Currently, the successfulmanagement of many retinal diseases often requires multiple intravitrealinjections of medication per year. Retinal diseases, such as diabeticretinopathy and age-related macular degeneration, among others, continueto represent major causes of irreversible vision loss in the UnitedStates. The treatment of these conditions is complicated by thedifficulty of delivering medications to the retina. The direct deliveryof drugs to the vitreous chamber has become an important tool in thearsenal of retinal disease management.

Unfortunately, the chronic and progressive nature of many retinaldiseases necessitates repeated injections to provide continuedtreatment. The current regimens, which vary based on the disease, itsstage, and the medications used, can include up to six intraocularinjections per year. Each intravitreal injection, however, is associatedwith the risk of developing serious and vision-threatening infectionsand even traumatic retinal injury.

SUMMARY

In one aspect, the invention provides methods for treating eye disordersin a patient in need thereof. The methods can include, for example,administering a drug delivery system into an eye compartment of thepatient, the drug delivery system having (i) a particle including acore; (ii) a coating associated with the particle, wherein the coatingis covalently or non-covalently associated with the particle andpresents a hydrophilic region to the environment around the particle;and (iii) a therapeutically effective amount of a therapeutic agent,thereby treating the eye disorder. In some embodiments, the eyecompartment exhibits reduced inflammation or IOP than if a drug deliverysystem using an uncoated particle were administered to the patient. Theinflammation or IOP can be reduced by, for example, at least about 10%,or at least about 30%, or at least about 50%. In some embodiments, thecore includes a biocompatible polymer.

In some embodiments, the coating includes one or more molecules havinghydrophilic regions and hydrophobic regions. For example, at least about50% of the hydrophobic regions in the coating molecules have a molecularmass of least about 2 kDa, or at least about 3 kDa. The hydrophobicregions can include, for example, PPO. The hydrophilic regions caninclude, for example, PEG. The particles can have a diameter of, forexample, less than about 100,000 nm, or less than about 50,000 nm, orless than about 10,000 nm, or less than about 5,000 nm, or less thanabout 1,000 nm. In some embodiments, the particle has a diameter ofabout 200 nm.

The particle can include, for example, a biodegradable polymer such aspoly(lactic-co-glycolic acid). The coating can be, for example, boundcovalently to the particle, or it can be non-covalently associated withthe particle. In some embodiments, the coating includes one or more ofPluronic P103, Pluronic P105, and poloxamer 407.

In some embodiments, administering the drug delivery system involvesinjecting the drug delivery system into an eye compartment, such as thevitreous chamber, the sclera, the stroma or the anterior chamber. Thedrug delivery system can include a therapeutic agent such as one or moreof an anti-inflammatory drug, an antimicrobial agent, ananti-angiogenesis agent, an immunosuppressant, an antibody, an antibodyfragment, a steroid, a chemotherapeutic agent, an ocularanti-hypertensive drug and combinations thereof. In some embodiments,the drug delivery system provides sustained release of the therapeuticagent over a period of time, for example at least about 1 day, or atleast about 1 week, or at least about 4 weeks.

In another aspect, the invention provides drug delivery systems. Thedrug delivery system can include: (i) a particle including a core; (ii)a coating associated with the particle, wherein the coating iscovalently or non-covalently associated with the particle and presents ahydrophilic region to the environment around the particle; and (iii) atherapeutically effective amount of a therapeutic agent. The drugdelivery system can be suitable for administration into an eyecompartment, such as the vitreous chamber, the sclera, the cornealstroma and the anterior chamber. The core can include, for example, abiocompatible polymer. In some embodiments, the drug delivery systembrings about reduced inflammation or IOP when administered to thepatient than if a drug delivery system using an uncoated particle wereadministered to the patient, for example by at least about 10%, or atleast about 30%, or at least about 50%. In some embodiments, the coatingincludes one or more molecules having hydrophilic regions andhydrophobic regions. For example, at least about 50% of the hydrophobicregions in the coating molecules have a molecular mass of least about 2kDa, or at least about 3 kDa. In some embodiments, the hydrophobicregions comprise PPO. In some embodiments, the hydrophilic regionscomprise PEG. The particle can include, for example, a biodegradablepolymer such as poly(lactic-co-glycolic acid). The coating can include,for example, one or more of Pluronic P103, Pluronic P105 and poloxamer407. The particles can have a diameter of, for example, less than about100,000 nm, or less than about 50,000 nm, or less than about 10,000 nm,or loss than about 5,000 nm, or less than about 1,000 nm. In someembodiments, the particle has a diameter of about 200 nm. In someembodiments, the therapeutic agent is one or more of ananti-inflammatory drug, an antimicrobial agent, an anti-angiogenesisagent, an immunosuppressant, an antibody, an antibody fragment, asteroid, a chemotherapeutic agent, an ocular anti-hypertensive drug andcombinations thereof. The drug delivery system can be suitable foradministration into the eye compartment by injection.

The drug delivery system can also include, for example, (i) a substrate;(ii) a coating associated with the substrate, wherein the coatingpresents a hydrophilic region to the environment around the substrate;and (iii) a therapeutically effective amount of a therapeutic agent. Thedrug delivery system can, for example, bring about reduced inflammationwhen administered to the patient than if a drug delivery systemcomprising an uncoated substrate were administered to the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph depicting the inflammation profile in female NewZealand white rabbits after intracameral injection of severalparticle-coating combinations according to the compositions and methodsdisclosed herein.

DETAILED DESCRIPTION

The presently disclosed subject matter may be embodied in massydifferent forms and should not be construed as limited to theembodiments set forth herein. Indeed, many modifications and otherembodiments of the presently disclosed subject matter will come to mindfor one skilled in the art to which the presently disclosed subjectmatter pertains having the benefit of the teachings presented in thedescriptions included herein. Therefore, it is to be understood that thepresently disclosed subject matter is not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the disclosed subjectmatter.

Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this presently described subject matter belongs.

Following long-standing patent law convention, the terms “a,” “an,” and“the” refer to “one or more” when used in this application, includingthe claims. Thus, for example, reference to “a subject” includes one ora plurality of subjects, unless the context clearly is to the contrary(e.g., a plurality of subjects), and so forth.

Throughout the specification and claim(s), the terms “comprising,”“having,” “including,” or “containing” and any grammatical derivationsthereof, are intended to be non-limiting, i.e., they are inclusive oropen-ended, such that recitation of particular elements in a list doesnot exclude other like, but unrecited, elements that can be substitutedor added to the recited elements.

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing amounts, sizes, dimensions,proportions, shapes, formulations, parameters, percentages, parameters,quantities, characteristics, and other numerical values used in thespecification and claims, are to be understood as being modified in allinstances by the term “about” even though the term “about” may notexpressly appear with the value, amount or range. Accordingly, unlessindicated to the contrary, the numerical parameters set forth in thefollowing specification and attached claims are not and need not beexact, but may be approximate and/or larger or smaller as desired,reflecting tolerances, conversion factors, rounding off, measurementerror and the like, and other factors known to those of skill in the artdepending on the desired properties sought to be obtained by thepresently disclosed subject matter. For example, the term “about,” whenreferring to a value can be meant to encompass variations of, in someembodiments, ±100%; in some embodiments, ±50%; in some embodiments,±20%; in some embodiments, ±10%; in some embodiments, ±5%; in someembodiments, ±1%; in some embodiments, ±0.5%; and in some embodiments,±0.1% from the specified amount, as such variations are appropriate toperform the disclosed methods or employ the disclosed compositions.

Further, the term “about” when used in connection with one or morenumbers or numerical ranges, should be understood to refer to all suchnumbers, including all numbers in a range and modifies that range byextending the boundaries above and below the numerical values set forth.The recitation of numerical ranges by endpoints includes all numbers,e.g., whole integers, including fractions thereof, subsumed within thatrange (for example, the recitation of 1 to 5 includes 1, 2, 3, 4, and 5,as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like)and any range within that range.

In one aspect, methods for treating one or more eye disorders aredisclosed. The methods can involve, for example, administering a drugdelivery system into an eye compartment of a patient. In someembodiments, the drug delivery system can include: i) a particlecontaining a core; ii) a coating disposed on the surface of theparticle, wherein the coating molecules have hydrophilic regions; andiii) a therapeutic agent, for example a therapeutically effective amountof a therapeutic agent. The coating molecules can include, for example,hydrophobic regions. In some embodiments, at least about 50% of thehydrophobic regions in the coating molecules have a molecular mass ofleast about 2 kDa. In some embodiments, the drug delivery system caninclude a particle and a coating; and in some embodiments, a particle,coating and therapeutic agent. The drug delivery system can contain, forexample, a pharmaceutically acceptable carrier. The drug delivery systemcan be suitable for administration into an eye compartment of a patient,for example by injection into the eye compartment. In some embodiments,the core includes a biocompatible polymer. As used herein, unless thecontext indicates otherwise, “drug delivery system” and “particlecomposition” can be used interchangeably.

The particle in the drug delivery system can be of various sizes. Theappropriate particle size can vary based on the method ofadministration, the eye compartment to which the drug delivery system isadministered, the therapeutic agent employed and the eye disorder to betreated, as will be appreciated by a person of skill in the art in lightof the teachings disclosed herein. For example, in some embodiments theparticle has a diameter of at least about 1 nm, or from about 1 nm toabout 50 microns. The particle can also have a diameter of, for example,from about 1 nm to about 30 microns; or from about 1 nm to about 10microns; or from about 1 nm to about 6 microns; from about 1 nm to about5 microns; or from about 1 nm to about 3 microns; or from about 1 nm toabout 1000 nm; or from about 25 nm to about 750 nm; or from about 50 nmto about 500 nm; or from about 100 nm to about 300 nm. In someembodiments, the average particle size can be about 1 nm, about 10 nm,about 50 nm, about 100 nm, about 150 nm, about 200 nm, about 250 nm,about 300 nm, about 350 nm, about 400 nm, about 450 nm, about 500 nm,about 550 nm, about 600 nm, about 650 nm, about 700 nm, about 750 nm,about 800 nm, about 850 nm, about 900 nm, about 950 nm, or about 1000nm, or about 2,000 nm, or about 5,000 nm, or about 6,000 nm, or about10,000 nm, or about 20,000 nm, or about 50,000 nm, or about 100,000 nm.In some embodiments, the particle size can be about 100 microns or less,about 50 microns or less, about 30 microns or less, about 10 microns orless, about 6 microns or less, about 5 microns or less, about 3 micronsor less, about 1000 nm or less, about 800 nm or leas, about 600 nm orless, about 500 nm or less, about 400 nm or less, about 300 nm or less,about 200 nm or less, or about 100 nm or less. In some embodiments, theparticle con be a nanoparticle or a microparticle, as these terms aredefined herein. In some embodiments, the drug delivery system cancontain a plurality of particles. The particles can be allnanoparticles, all microparticles, or a combination of nanoparticles andmicroparticles.

In some embodiments, the drug delivery system includes a particlecomprising a core. The core can be, for example, a small molecule, apolymer, a lipid, a protein, a carbohydrate, a viral carrier, avirosome, a sterol, a liposome, a metal, a metal oxide (e.g., silica), aquantum dot, a therapeutic agent in pure or substantially pure form(e.g., in crystal form), and the like, as well as any combination of anyof the foregoing. The particle can include, without limitation, one ormore lipid based drug carriers.

The particles of the drug delivery system can include a biocompatiblepolymer. As used herein, the term “biocompatible polymer” encompassesany polymer that can be administered to a patient without adverseeffects to the patient, or for which any adverse effects are deemed by aperson having ordinary skill in the art to be outweighed by the benefitsbrought about by the drug delivery system in light of the mode ofadministration, the therapeutic agent employed, and/or the eye disorderto be treated, and also when considered in light of the availability ofalternative therapeutic regimen and their characteristics.

Examples of biocompatible polymers include but are not limited topolystyrenes; poly(hydroxy acid); poly(lactic acid); poly(glycolicacid); poly(lactic acid-co-glycolic acid); poly(lactic-co-glycolicacid); poly(lactide); poly(glycolide); poly(lactide-co-glycolide);polyanhydrides; polyorthoesters; polyamides; polycarbonates;polyalkylenes; polyethylenes; polypropylene; polyalkylene glycols;poly(ethylene glycol); polyalkylene oxides; poly(ethylene oxides);polyalkylene terephthalates; poly(ethylene terephthalate); polyvinylalcohols; polyvinyl ethers; polyvinyl esters; polyvinyl halides;poly(vinyl chloride); polyvinylpyrrolidone; polysiloxanes; poly(vinylalcohols); poly(vinyl acetate); polyurethanes; co-polymers ofpolyurethanes; derivativized celluloses; alkyl cellulose; hydroxyalkylcelluloses; cellulose ethers; cellulose esters; ultra celluloses; methylcellulose; ethyl cellulose; hydroxypropyl cellulose; hydroxy-propylmethyl cellulose; hydroxybutyl methyl cellulose; cellulose acetate;cellulose propionate; cellulose acetate butyrate; cellulose acetatephthalate; carboxylethyl cellulose; cellulose triacetate; cellulosesulfate sodium salt; polymers of acrylic acid; methacrylic acid;copolymers of methacrylic acid; derivatives of methacrylic acid;poly(methyl methacrylate); poly(ethyl methacrylate);poly(butylmethacrylate); poly(isobutyl methacrylate);poly(hexylmethacrylate); poly(isodecyl methacrylate); poly(laurylmethacrylate); poly(phenyl methacrylate); poly(methyl acrylate);poly(isopropyl acrylate); poly(isobutyl acrylate); poly(octadecylacrylate); poly(butyric acid); poly(valeric acid);poly(lactide-co-caprolactone); copolymers ofpoly(lactide-co-caprolactone); blends of poly(lactide-co-caprolactone);hydroxyethyl methacrylate (HEMA); copolymers of HEMA with acrylate;copolymers of HEMA with polymethylmethacrylate (PMMA);polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA); acrylatepolymers/copolymers; acrylate/carboxyl polymers; acrylate hydroxyland/or carboxyl copolymers; polycarbonate-urethane polymers;silicone-urethane polymers; epoxy polymers; cellulose nitrates;polytetramethylene ether glycol urethane;polymethylmethacrylate-2-hydroxyethylmethacrylate copolymer;polyethylmethacrylate-2-hydroxyethylmethacrylate copolymer;polypropylmethacrylate-2-hydroxyethylmethacrylate copolymer;polybutylmethacrylate-2-hydroxyethylmethacrylate copolymer;polymethylacrylate-2-hydroxyethylmethacrylate copolymer;polyethylacrylate-2-hydroxyethylmethacrylate copolymer;polypropylacrylate-2-hydroxymethacrylate copolymer;polybutylacrylate-2-hydroxyethylmethacrylate copolymer;copolymermethylvinylether maleicanhydride copolymer; poly(2-hydroxyethyl methacrylate) acrylate polymer/copolymer; acrylatecarboxyl and/or hydroxyl copolymer; olefin acrylic acid copolymer;ethylene acrylic acid copolymer; polyamide polymers/copolymers;polyimide polymers/copolymers; ethylene vinylacetate copolymer;polycarbonate urethane; silicone urethane; polyvinylpyridine copolymers;polyether sulfones; polygalactin, poly-(isobutyl cyanoacrylate), andpoly(2-hydroxyethyl-L-glutamine); polydimethyl siloxane;poly(caprolactones); poly(ortho esters); polyamines; polyethers;polyesters; polycarbamates; polyureas; polyimides; polysulfones;polyacetylenes; polyethyeneimines; polyisocyanates; polyacrylates;polymethacrylates; polyacrylonitriles; polyarylates; and combinations,copolymers and/or mixtures of two or more of any of the foregoing. Insome cases, the particle includes a hydrophobic material and at leastone bioactive agent. In certain embodiments, the hydrophobic material isused instead of a polymer. In other embodiments, the hydrophobicmaterial is used in addition to a polymer.

In some embodiments, the presently disclosed particles contain abiodegradable polymer. The biodegradable polymer can contain a syntheticpolymer, although natural polymers also can be used. The polymer can be,for example, poly(lactic-co-glycolic acid) (PLGA), polystyrene orcombinations thereof. The polystyrene can, for example, be modified withcarboxyl groups. Other examples of biodegradable polymers includepoly(hydroxy acid); poly(lactic acid); poly(glycolic acid); poly(lacticacid-co-glycolic acid); poly(lactide); poly(glycolide);poly(lactide-co-glycolide); polyanhydrides; polyorthoesters; polyamides;polycarbonates; polyalkylenes; polyethylene; polypropylene; polyalkyleneglycols; poly(ethylene glycol); polyalkylene oxides; poly(ethyleneoxides); polyalkylene terephthalates; poly(ethylene terephthalate);polyvinyl alcohols; polyvinyl ethers; polyvinyl esters; polyvinylhalides; poly(vinyl chloride); polyvinylpyrrolidone; polysiloxanes;poly(vinyl alcohols); poly(vinyl acetate); polyurethanes; co-polymers ofpolyurethanes; derivativized celluloses; alkyl cellulose; hydroxyalkylcelluloses; cellulose ethers; cellulose esters; nitro celluloses; methylcellulose; ethyl cellulose; hydroxypropyl cellulose; hydroxy-propylmethyl cellulose; hydroxybutyl methyl cellulose; cellulose acetate;cellulose propionate; cellulose, acetate butyrate; cellulose acetatephthalate; carboxylethyl cellulose; cellulose triacetate; cellulosesulfate sodium salt; polymers of acrylic acid; methacrylic acid;copolymers of methacrylic acid; derivatives of methacrylic acid;poly(methyl methacrylate); poly(ethyl methacrylate);poly(butylmethacrylate); poly(isobutyl methacrylate);poly(hexylmethacrylate); poly(isodecyl methacrylate); poly(laurylmethacrylate); poly(phenyl methacrylate); poly(methyl acrylate);poly(isopropyl acrylate); poly(isobutyl acrylate); poly(octadecylacrylate); poly(butyric acid); poly(valeric acid);poly(lactide-co-caprolactone); copolymers ofpoly(lactide-co-caprolactone); blends of poly(lactide-co-caprolactone);polygalactin; poly-(isobutyl cyanoacrylate);poly(2-hydroxyethyl-L-glutam-nine); and combinations, copolymers and/ormixtures of one or more of any of the foregoing. Furthermore, as aperson of ordinary skill in the art would appreciate, some of thepolymers listed above as “biocompatible” can also be consideredbiodegradable, whether or not they are included in the above listing ofrepresentative biodegradable polymers. As used herein, “derivatives”include polymers having substitutions, additions of chemical groups andother modifications routinely made by those skilled in the art.

In some embodiments, the drug delivery systems contain a particle with acoating on the surface, wherein the coating molecules have hydrophilicregions and, optionally, hydrophobic regions, wherein the coatedparticle causes less inflammation than a similar, but uncoated particle,as measured by standard protocols, for example upon injection into theanterior chamber of a New Zealand white rabbit or a human.

The drug delivery system can also include a coating. The coating can bedisposed on the surface of the particle, for example by bonding,adsorption or by compilation. The coating can also be intermingled ordispersed within the particle as well as disposed on the surface of theparticle.

The coating can be, for example, polyethylene glycol, polyvinyl alcohol(PVA), or similar substances. The coating can be, for example, vitaminE-PEG 1 k or vitamin E-PEG 5 k or the like. Vitamin E-PEG 5 k can helppresent a dense coating of PEG on the surface of a particle. The coatingcan also include nonionic surfactants such as those composed ofpolyaklyene oxides, e.g., polyoxyethylene (PEO), also referred to hereinas polyethylene glycol; or polyoxypropylene (PPO), also referred toherein as polypropylene glycol (PPG), and can include co-polymers ofmore than one alkylene oxide. The copolymers can be, for example, randomcopolymers, block copolymers or graft copolymers. In some embodiments,the coating includes a polyoxyethylene-polyoxypropylene copolymer, e.g.,block copolymers of ethylene oxide and propylene oxide. (i.e.,poloxamers). Examples of poloxamers suitable for use in the coatingsinclude, for example, poloxamers 188, 237, 338 and 407. These poloxamersare available under the trade name Pluronic® (available from BASF, MountOlive, N.J.) and correspond to Pluronic® F-68, F-87, F-108 and F-127,respectively. Poloxamer 188 (corresponding to Pluronic® F-68) is a blockcopolymer with an average molecular mass of about 7,000 to about 10,000Da, or about 8,000 to about 9,000 Da, or about 8,400 Da. Poloxamer 237(corresponding to Pluronic® F-87) is a block copolymer with an averagemolecular mass of about 6,000 to about 9,000 Da, or about 6,500 to about8,000 Da, or about 7,700 Da. Poloxamer 338 (corresponding to Pluronic®F-108) is a block copolymer with an average molecular mass of about12,000 to about 18,000 Da, or about 13,000 to about 15,000 Da, or about14,600 Da. Poloxamer 407 (corresponding to Pluronic® F-127) is apolyoxyethylene-polyoxypropylene triblock copolymer in a ratio ofbetween about E₁₀₁ P₅₆ E₁₀₁ to about E₁₀₆ P₇₀ E₁₀₆, or about E₁₀₁ P₅₆E₁₀₁, or about E₁₀₆ P₇₀ E₁₀₆, with an average molecular mass of about10,000 to about 15,000 Da, or about 12,000 to about 14,000 Da, or about12,000 to about 13,000 Da, or about 12,600 Da. For example, the NF formsof poloxamers or Pluronic® polymers can be used.

In some embodiments, the coating can be, for example Pluronic® P103 orPluronic® P105. Pluronic® P103 is a block copolymer with an averagemolecular mass of about 3,000 Da to about 6,000 Da, or about 4,000 Da toabout 6,000 Da, or about 4,950 Da. Pluronic® P105 is a block copolymerwith an average molecular mass of about 5,000 Da to about 8,000 Da, orabout 6,000 Da to about 7,000 Da, or about 6,500 Da.

In some embodiments, the coating can have an average molecular weight ofabout 9,000 Da or greater, about 10,000 Da or greater, about 11,000 Daor greater or about 12,000 Da or greater. In exemplary embodiments, thecoating can have an average molecular weight of from about 10,000 toabout 15,000 Da, or about 12,000 to about 14,000 Da, or about 12,000 toabout 13,000 Da, or about 12,600 Da. In some embodiments, the coatingcan be selected from Pluronic® P103, P105, F-68, F-87, F-108 and F-127,from Pluronic® P103, P105, F-87, F-108 and F-127, or from Pluronic®P103, P105, F-108 and F-127, or from Pluronic® P103, P105 and F-127. Insome embodiments, the coating can be Pluronic® F-127. In representativeembodiments, the coating is associated with the particles. For example,the coating can be covalently attached to the particles. Inrepresentative embodiments, the coating is polyethylene glycol, which iscovalently attached to the particle, yielding what is commonly referredto as a PEGylated particle.

In some embodiments, the coating is non-covalently associated with theparticle. This association can be held together by any force ormechanism of molecular interaction that permits two substances to remainin substantially the same positions relative to each other, includingintermolecular forces, dipole-dipole interactions, van der Waals forces,hydrophobic interactions, electrostatic interactions and the like. Insome embodiments, the coating is adsorbed onto the particle. Accordingto representative embodiments, a non-covalently bound coating can becomprised of portions or segments that promote association with theparticle, for example by electrostatic or van der Waals forces. In someembodiments, the interaction is between a hydrophobic portion of thecoating and the particle. Embodiments include particle coatingcombinations which, however attached to the particle, present ahydrophilic region, e.g. a PEG rich region, to the environment aroundthe particle coating combination. The particle coating combination canprovide both a hydrophilic surface and an uncharged or substantiallyneutrally-charged surface, which can be biologically inert.

Suitable coatings for use according to the compositions and methodsdisclosed herein can be made up of molecules having hydrophobic regionsas well as hydrophilic regions. Without wishing to be bound by anyparticular theory, it is believed that the hydrophobic regions of thecoating molecules are able to form adsorptive interactions with thesurface of the particle, and thus maintain a non-covalent associationwith it, while the hydrophilic regions orient toward the surrounding,frequently aqueous, environment. In some embodiments the hydrophilicregions are characterized in that they avoid or minimize adhesiveinteractions with substances in the surrounding environment. Suitablehydrophobic regions in the coatings can include, for example, PPO,vitamin E and the like, either alone or in combination with each otheror with other substances. Suitable hydrophilic regions in the coatingscan include, for example, PEG, heparin, polymers that form hydrogels andthe like, alone or in combination with each other or with othersubstances.

Representative coatings according to the compositions and methodsdisclosed herein can include molecules having, for example, hydrophobicsegments such as PPO segments with molecular weights of at least about1.8 kDa, or at least about 2 kDa, or at least about 2.5 kDa, or at leastabout 3 kDa, or at least about 3.5 kDa, or at least about 4.0 kDa, or atleast about 4.5 kDa, or at least about 5.0 kDa or more. In someembodiments, the coatings can have PPO segments with molecular weightsof from about from about 1.8 kDa to about 10 kDa, or from about 2 kDa toabout 5 kDa, or from about 2.5 kDa to about 4.5 kDa, or from about 2.5kDa to about 3.5 kDa. In some embodiments, at least about 10%, or atleast about 25%, or at least about 50%, or at least about 75%, or atleast about 90%, or at least about 95%, or at least about 99% or more ofthe hydrophobic regions in these coatings have molecular weights withinthese ranges. In some embodiments, the coatings are biologically inert.Compounds that generate both a hydrophilic surface and an uncharged orsubstantially neutrally-charged surface can be biologically inert.

In some embodiments, the coating can include, for example, one or moreof the following: anionic proteins (e.g., bovine serum albumin),surfactants (e.g., cationic surfactants such as for exampledimethyldioctadecyl-ammonium bromide), sugars or sugar derivatives(e.g., cyclodextrin), nucleic acids, polymers (e.g., heparin), mucolyticagents, N-acetylcysteine, mugwort, bromelain, papain, clerodendrum,acetylcysteine, bromhexine, carbocisteine, eprazinone, mesna, ambroxol,sobrerol, domiodol, letosteine, stepronin, tiopronin, gelsolin, thymosinβ4, dornase alfa, neltenexine, erdosteine, various DNases includingrhDNase, agar, agarose, alglnic acid, amylopectin, amylose, beta-glucan,callose, carrageenan, cellodextrins, cellulin, cellulose, chitin,chitosan, chrysolaminarin, curdlan, cyclodextrin, dextrin, ficoll,fructan, fucoidan, galactomannan, gellan gum, glucan, glucomannan,glycocalyx, glycogen, hemicellulose, hydroxyethyl starch, kefiran,laminarin, mucilage, glycosaminoglycan, natural gum, paramylon, pectin,polysaccharide peptide, schizophyllan, sialyl lewis x, starch, starchgelatinization, sugammadex, xanthan gum, xyloglucan,L-phosphatidylcholine (PC), 1,2-dipalmitoylphosphatidycholine (DPPC),oleic acid, sorbitan trioleate, sorbitol monooleate, sorbitanmonolaurate, polyoxyethylent (20) sorbitan monolaurate, polyoxyethylene(20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2)ether, stearyl polyoxyethylene (2) ether, polyoxyethylene (4) laurylether, block copolymers of oxyethylene and oxypropylene, syntheticlecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyloleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate,glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethyleneglycol 400, cetyl pyridinium chloride, benzalkonium chloride, olive oil,glyceryl monolaurate, corn oil, cotton seed oil, sunflower seed oil,lecithin, oleic acid, sorbitan trioleate, and combinations of two ormore of any of the foregoing.

The particle-coating combinations can be made up of any combination ofparticle and coating substances disclosed or suggested herein. Examplesof such combinations include, for example, polystyrene-PEG, orPLGA-Pluronic® F-127.

In some embodiments, the coating is associated with the particle, eitherthrough covalent or non-covalent interactions with the particle.Coatings that can be covalently bound to the particle include, forexample, PEG. PEG can be covalently bound to any suitable polymer thatcan be included in the particle. An example of a polymer that can becoated with PEG is polystyrene. Other particles that can be PEGylatedare known in the art.

The drug delivery system can include one or more therapeutic agents. Anytherapeutic agent can be used which is suitable to administration in thedrug delivery system disclosed herein, as would be appreciated by aperson of ordinary skill. Examples of types of such therapeutic agentsinclude anti-inflammatory drugs, antimicrobial agents, anti-angiogenesisagents, immunosuppressants, antibodies, steroids, chemotherapeuticagents, ocular anti-hypertensive drugs and combinations thereof.Examples of therapeutic agents that can be used in the drug deliverysystem disclosed herein include acyclovir, amikacin, anecortane acetate,anthracenedione, anthracycline, an azole, amphotericin B, bevacizumab,camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidinedigluconate, clortrimazole, a clotrimazole cephalosporin,corticosteroids, dexamethasone, desamethazone, econazole, eftazidime,epipodophyllotoxin, fluconazole, flucytosine, fluoropyrimidines,fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itraconazole,ivermectin, ketoconazole, levofloxacin, macrolides, miconazole,miconazole nitrate, moxifloxacin, natamycin, neomycin, nystatin,ofloxacin, polyhexamethylene biguanide, prednisolone, prednisoloneacetate, pegaptanib, platinum analogues, polymicin B, propamidineisethionate, pyrimidine nucleoside, ranibizumab, squalamine lactate,sulfonamides, triamcinolone, triamcinolone acetonide, triazoles,vancomycin, anti-vascular endothelial growth factor (VEGF) agents, VEGFantibodies, VEGF antibody fragments, vines alkaloid, timolol, betaxolol,travoprost, latanoprost, bimatoprost, brimonidine, dorzolamide,acetazolamide, pilocarpine, ciprofloxacin, azithromycin, gentamycin,tobramycin, cefazolin, voriconazole, gancyclovir, cidofovir, foscarnet,diclofenac, nepafenac, ketorolac, ibuprofen, indomethacin,fluoromethalone, rimexolone, anecortave, cyclosporine, methotrexate,tacrolimus and combinations thereof.

The drug delivery systems disclosed herein, which can include one ormore therapeutic agents, can be used to treat eye disorders according tothe methods disclosed herein. The drug delivery system can be used totreat any eye disorder that, in the judgment of a person of ordinaryskill in the art, would be effectively treated with any of the drugdelivery systems disclosed herein. Examples of eye disorders that may betreated according to the compositions and methods disclosed hereininclude amoebic keratitis, fungal keratitis, bacterial keratitis, viralkeratitis, onchorcercal keratitis, bacterial keratoconjunctivitis, viralkeratoconjunctivitis, corneal dystrophic diseases, Fuchs' endothelialdystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dryeye diseases, environmental dry eye diseases, corneal neovascularizationdiseases, post-corneal transplant rejection prophylaxis and treatment,autoimmune uveitis, infectious uveitis, anterior uveitis, posterioruveitis (including toxoplasmosis), pan-uveitis, an inflammatory diseaseof the vitreous or retina, endophthalmitis prophylaxis and treatment,macular edema, macular degeneration, age related macular degeneration,proliferative and non-proliferative diabetic retinopathy, hypertensiveretinopathy, an autoimmune disease of the retina, primary and metastaticintraocular melanoma, other intraocular metastatic tumors, open angleglaucoma, closed angle glaucoma, pigmentary glaucoma and combinationsthereof.

According to the methods disclosed herein, the drug delivery system canbe administered into an eye compartment of a patient with an eyedisorder. The drug delivery system can be administered to any eyecompartment that is susceptible to an eye disorder treatable with thecompositions and methods disclosed herein. Examples of such eyecompartments include the vitreous chamber, subretinal space,subchoroidal space, the episclera, the conjunctiva, the sclera, theanterior chamber, and the cornea and compartments therein (e.g.,subepithelial, intrastromal, endothelial).

The drug delivery system can be administered via any route which iseffective to deliver an effective amount of the therapeutic agent to theeye compartment to be treated. For example, the drug delivery system canbe injected into the eye compartment to be treated, such as, forexample, the vitreous chamber, subretinal space, subchoroidal space, theepiselera, the conjunctiva, the sclera or the anterior chamber, and thecornea and compartments therein (e.g., subepithelial, intrastromal,endothelial).

The drug delivery systems disclosed herein provide sustained release ofa therapeutic agent over a period of time. For example, alteradministration of the drug delivery system, the therapeutic agent can bereleased for at least about 6 hours, at least about 12 hours, at leastabout 1 day, at least about 2 days, at least about 3 days, at leastabout one week, at least about 2 weeks, at least about 3 weeks, at leastabout 4 weeks, at least about 5 weeks, at least about 6 weeks, at leastabout 7 weeks, at least about 2 months, at least about 3 months, atleast about 6 months, at least about 9 months, at least about 1 year ormore. Furthermore, according to the compositions and methods disclosedherein, administration of the drug delivery systems to the patientcauses less inflammation or IOP over time than if other drug deliverysystems are administered. Notwithstanding the foregoing, there may besome initial inflammation shortly after administration, even with thedrug delivery system disclosed herein. However, a reduction ofinflammation or IOP can be observed after about 2 dayspost-administration, or after about 5 days post-administration.Inflammation or IOP is reduced over time, even with administration ofconventional or previously available drug delivery systems. However, thereduction or avoidance of inflammation or IOP when using methods andcompositions disclosed herein is persistent and can continue to beobserved for up to 30 days, up to 20 days, up to 15 days, or up to 10days post-administration. The reduction or avoidance of inflammation orIOP can continue for at least about 10 days, at least about 15 days, atleast about 20 days, or at least about 30 days post-administration.

In some embodiments, the drug delivery systems disclosed herein whenadministered to the vitreous chamber, the sclera, the anterior chamberor other eye compartment of a patient, achieve reduced or decreasedinflammation, and thus, for example, reduced intraocular pressure (IOP)over that which would be brought about if, for example, an uncoatedpolymer particle, for example a particle otherwise similar to the coatedparticle, were administered to same eye compartment in the patient.Furthermore, drug delivery systems including particles and coatingsaccording to the compositions and methods disclosed herein can reduce oravoid an increase in IOP over that which would be observed if uncoatedparticles of similar size were administered. Accordingly, the particlesize threshold for inducing or increasing IOP can be higher for coatedparticles than it would be for uncoated particles. As a result, it maybe possible to use larger particles for administration into an eyecompartment, for example into the AC, if such particles are coatedaccording to the compositions and methods disclosed herein. In someembodiments, the drug delivery systems disclosed herein provide theadvantage of avoiding or reducing aggregation of particles afteradministration.

Inflammation and IOP can be measured after administration of thecompositions disclosed herein by methods known in the art. For example,a Reichert Tono-Pen contact tonometer can be used to assess the IOP, andchanges in IOP, in any eye compartment disclosed herein, for example theAC. The subjects, for example animals, can be evaluated on severalpost-injection days, for example at 1, 7, 14 and 30 days post-injectionusing the same evaluation procedure on each day. One or moremeasurements, for example about five, can be obtained for each subjectat each time point. When measuring IOP according to methods known in theart, for example the method described above, IOP is shown to be reducedby, for example, at least about 10%, or at least about 30%, or at leastabout 50% over what is observed when a drug delivery system using anuncoated particle, for example a particle that is otherwise similar tothe coated particle, is administered to the patient. To measureinflammation, Slit-lamp biomicroscopy can be performed to examine anyeye compartment disclosed herein, for example, the AC, for signs ofinflammation. The examination can involve observation of criteria suchas the presence of cells, flare and fibrin. The subjects can beevaluated on several post-injection days, for example at 1, 7, 14 and 30days post-injection using the same evaluation procedure on each day.After general and/or local anesthesia is achieved, each subject can beexamined for gross abnormalities. The exams can be performed by the sametrained ophthalmologist, and the ophthalmologist can be blinded to theassignment of the treatment and control subjects. Quantification ofinflammation of an eye compartment such as the AC can be performed usinga modified version of the Standard Uveitis Nomenclature clinical gradingscheme, as detailed more fully in the examples. When measuringinflammation according to methods known in the art, for example themethod described above, inflammation is shown to be reduced by, forexample, at least about 10%, or at least about 30%, or at least about50% over what is observed when a drug delivery system using an uncoatedparticle, for example a particle that is otherwise similar to the coatedparticle, is administered to the patient. When comparing an IOP orinflammation measurement obtained after administration of a coatedparticle versus an IOP or inflammation measurement obtained for anuncoated particle, the measurements compared can, and frequently should,be taken at similar time points post injection. For example, an IOPmeasurement for a coated particle taken 7 days post-injection isgenerally compared with an IOP measurement for an uncoated particletaken 7 days post-injection.

A further advantage of certain embodiments of the drug delivery systemsdisclosed herein is that they can be composed of generally recognized assafe (GRAS) materials, without the formation of new chemical entitles(NCEs). Avoidance of NCE formation can be an advantage because NCEs canbe subject to a lengthy and expensive regulatory review process beforethey are permitted to be marketed.

As described in detail in the Examples, the particle compositions can beretained within an eye compartment, including for example the stroma,the anterior chamber or the vitreous chamber for periods of time greaterthan those observed with free-standing drugs. Furthermore, coatedparticle compositions can exhibit increased retention over uncoatedparticle compositions. This effect is seen in particles withcovalently-attached coatings, for example PEG-coated particles, as wellas in particles with non-covalently associated coatings, of whichPluronic® PF-127-coated particles are representative, and indeed theextent of the effect can be very similar for covalently-attached andnon-covalently associated coatings (see FIG. 1). FIG. 1 alsodemonstrates that this effect is also seen in particle compositions madewith PLGA particles as well as those made with polystyrene particles.Furthermore, the increased retention is observed with polystyreneparticles covalently coated with PEG coating as well as in PLGAparticles with non-covalently associated. Pluronic® PF-127 coating.Accordingly, where increased retention is demonstrated for one type ofparticle composition, for example, covalently-PEGylated polystyreneparticles—one of ordinary skill in the art may expect that similarresults would be obtained for other types of particle compositions,e.g., PLGA particles non-covalently coated wish a poloxamer. Forinstance, as shown in the examples, PEGylated polystyrene particlesbehave similarly to and can serve as a model for PLGA particles withnon-covalently associated coatings such as Pluronic® PF-127 coating.These findings are consistent with the art usage of polystyreneparticles as models for other biocompatible particles and polymers.

Topically-administered medications to the eye often exhibit a poorability to penetrate the corneal stroma. Further, free-standing drugs,when injected into the corneal stroma, are cleared rapidly by diffusion,thereby limiting the amount of time the medication remains attherapeutic concentrations at the site of the injection. In someembodiments, the presently disclosed subject matter demonstrates, forexample, that intrastromally injected particle compositions can beretained with the corneal stroma for periods of time greater thanfree-standing drugs. For example, 200-nm and 1-μm latex particlesinjected intrastromally into living rabbits exhibited approximately 20%retention after two weeks. Uncoated 200-nm latex particles, however,caused substantial fibrin aggregation suggestive of inflammation afterintraocular injection is living rabbits. By varying size and surfacechemistry in accordance with the principles set forth herein, particlescan be engineered to reduce or avoid corneal inflammation and edema.

In some embodiments, the presently disclosed subject matter includesdelivery systems for intrastromal injection of medications that arecombined with the particles disclosed herein. Medications can include,but are not limited to, anti-inflammatory agents, antimicrobial agents,anti-angiogenesis agents, immunosuppressants, and/or combinationsthereof. Such combinations of medications can allow for the treatment ofconditions that require more than one medication. More particularly, insome embodiments, the presently disclosed subject matter includesparticle compositions containing anti-inflammatory agents for treatingand/or preventing inflammatory processes of the cornea. Some embodimentsof the presently disclosed subject matter include particle compositionscontaining immunosuppressant agents for preventing graft rejection aftercorneal transplantation.

In some embodiments, the presently disclosed subject matter includesparticles coated with and/or otherwise carrying antibodies, wherein theantibodies serve as a therapeutic agent and can be released over time.In some embodiments, the presently disclosed subject matter includesparticles combining a therapeutic antibody coating with othertherapeutic agents, e.g., one or more medications.

Further, the presently disclosed subject matter includes pharmaceuticalformulations including solutions of the presently disclosed particlecompositions, wherein the particles are combined with antibacterialagents, antifungal agents, anti-amoebic agents, antiviral agents, andcombinations thereof for treating and/or preventing infectious processesof the cornea. The presently disclosed subject matter also includespharmaceutical formulations including solutions of the presentlydisclosed particle compositions containing and/or coated withanti-angiogenesis agents (such as, for example, antibodies) for use inchronic inflammatory diseases of the cornea and/or other diseases thatcan lead to corneal neovascularization. Combinations of theabove-mentioned pharmaceutical formulations also are contemplated by thepresently disclosed subject matter.

In a representative embodiment, the presently disclosed subject matterprovides methods for treating keratitis, i.e., inflammations of thecornea, by injecting the presently disclosed particle compositionscontaining one or more therapeutic agents into the corneal stroma.Conditions treated by the presently disclosed methods include, but arenot limited to, amoebic keratitis, fungal keratitis, bacterialkeratitis, viral keratitis, and onchocercal keratitis.

Ameobic keratitis can be caused by acanthamoeba and can be treated byadministering to the corneal stroma of a subject in need of treatmentthereof the presently disclosed particle compositions containing one ormore anti-amoebic agents. Any anti-amoebic agent known in the art can becombined with the presently disclosed particle compositions.Representative, anti-amoebic agents include, but are not limited to,polyhexamethylene biguanide (PHMB), propamidine isethionate, miconazolenitrate, neomycin, chlorhexidine digluconate, polymicin B,clortrimazole, and combinations thereof.

Fungal keratitis can be caused by, for example, aspergillus fumigates,fusarium, and/or yeasts, such as candida, and can be treated byadministering to the corneal stroma of a subject in need of treatmentthereof the presently disclosed particle compositions containing one ormore anti-fungal agents. Any anti-fungal agent known in the art can becombined with the presently disclosed particle compositions.Representative, anti-fungal agents include, but are not limited to,natamycin, nystatin, amphotericin B, chlorhexidine, fluorinatedpyrimidines, such as flucytosine, azoles, such as imidazoles andtriazoles, including, but not limited to, ketoconazole, miconazole,itraconazole, fluconazole, econazole, and clotrimizole, and combinationsthereof.

Bacterial keratitis can be caused, for example, by Streptococcus,Pseudomonas, Enterobacteriaceae (including Klebsiella, Enterobacter,Serratia, and Proteus), and Staphylococcus species. Such infections canbe treated by administering to the corneal stroma of a subject in needof treatment thereof the presently disclosed particle compositionscontaining one or more anti-bacterial agents. Any anti-bacterial agentknown in the art can be combined with the presently disclosed particlecompositions. Representative, anti-bacterial agents include, but are notlimited to, cephalosporins, macrolides, glycopeptides, sulfonamides,chloramphenicol, fluoroquinolines, including, but not limited to,levofloxacin, gatifloxacin, moxifloxacin, and ofloxacin, andcombinations thereof.

Further, up to 20% of cases of fungal keratitis (particularlycandidiasis) can be complicated by bacterial co-infection. Thus, in someembodiments, the presently disclosed methods include combinationtherapies involving administering to the corneal stroma of a subject inneed of treatment thereof the presently disclosed particle compositionscontaining one or more anti-fungal agents and one or more anti-bacterialagents.

Viral keratitis can, for example, be caused by a herpes simplex virusand can be treated by administering to the corneal stroma of a subjectin need of treatment thereof the presently disclosed particlecompositions containing one or more anti-viral agents. Any anti-viralagent known in the art can be combined with the presently disclosedparticle compositions. A representative anti-viral agent includes, butis not limited to, acyclovir.

Onchoceral keratitis, also referred to as “River Blindness,” is causedby the nematode Onchocerca volvulus and can be treated by administeringto the corneal stroma of a subject in need of treatment thereof thepresently disclosed particle compositions containing one or moreanti-parasitic agents. Any anti-parasitic agent known in the art can becombined with the presently disclosed particle compositions. Arepresentative anti-parasitic agent includes, but is not limited to,ivermectin.

Further, representative embodiments of the presently disclosed methodsinclude a method for reversing or preventing graft rejection followingcorneal transplantation, the method involving administering to thecorneal stroma of a subject in need of treatment thereof the presentlydisclosed particle compositions containing one or more immunosuppressiveagents. Any immunospressive agent known in the art can be combined withthe presently disclosed particle compositions. Representativeimmunosuppressive agents include, but are not limited to,corticosteroids, such as doxamethasone and prednisolone acetate.

In some embodiments, the presently disclosed subject matter demonstratesthat, rather than injecting free-standing drugs into the anteriorchamber (AC) of an eye, particles injected into the AC can be retainedfor at least several weeks. The time period spans the entire duration oftypical post-operative treatment. By delivering medications combinedwith the presently disclosed particle compositions, the limitations oftopical and intracameral free drug injection can be eliminated. Thisapproach was limited in the past by particle-mediated increase inintraocular pressure (IOP) and inflammation responses. The presentlydisclosed subject matter overcomes these limitations by suitablymodifying particle size and/or surface chemistry.

For example, the presently disclosed subject matter demonstrates thatparticles injected directly into the AC of an eye can be retained forlong periods of time, thereby providing an effective vehicle forsustained ocular drug delivery. For example, the presently disclosedsubject matter demonstrates that 200-nm latex particles, covalentlycoated with a representative coating such as, for example, poly(ethyleneglycol), can be retained in the eyes of living rabbits for at least fourweeks with greater than 30% retention. Based on experiments disclosedherein, other coated particles described herein, for example PLGAnon-covalently coated with poloxamer, can bring about similar outcomes.In contrast, free drugs injected into the AC are cleared rapidly, forexample, at the same rate as the aqueous humor turnover.

Further, uncoated 200-nm latex particles caused substantial fibrinaggregation in the AC of living rabbits. The presently disclosed subjectmatter demonstrates that by suitably modifying size and/or surfacechemistry, particles can be engineered to avoid causing an increase inIOP and inflammation in the AC. For example, the presently disclosedsubject matter demonstrates that 200-nm latex particles, covalentlycoated with PEG, did not induce an increase in IOP after injection intothe AC of a living rabbit. Based on experiments disclosed herein, othercoated particles described herein, for example PLGA non-covalentlycoated with poloxamer, can bring about similar outcomes.

In some embodiments, the presently disclosed subject matter includesmedications for intracameral injection combined within particlesincluding, but not limited to, anti-inflammatory drugs, antimicrobials,anti-angiogenesis agents, immunosuppressants, and/or combinationsthereof. Such combinations of medications can allow for the treatment ofconditions that require more than one medication. For example, thepresently disclosed subject matter includes particle compositionscontaining anti-inflammatory agents alone or included withanti-angiogenesis agents for treating chronic corneal and/or anteriorchamber inflammatory processes. In some embodiments, the presentlydisclosed subject matter provides particle compositions containingimmunosuppressant agents either alone or in combination withanti-inflammatory agents and/or antimicrobial agents for use inpost-corneal transplant cases.

Further, the presently disclosed subject matter includes pharmaceuticalformulations containing solutions of the presently disclosed particlecompositions, wherein the particle compositions containanti-inflammatory and/or antimicrobial agents for injection aftercataract extraction or other ophthalmic surgeries. The presentlydisclosed subject matter also includes pharmaceutical formulations ofsolutions of the presently disclosed particle compositions, wherein theparticle compositions contain antibacterial, antifungal, amoebicidal,antiviral agents, or combinations thereof, for treating chronicinfectious processes of the cornea, and/or the anterior chamber.Combinations of the above-mentioned pharmaceutical formulations also arecontemplated by the presently disclosed subject matter.

For example, the presently disclosed subject matter provides a methodfor intracameral administration of the presently disclosed particlecompositions containing one or more therapeutic agents to an anteriorchamber of an eye of a subject in need of treatment thereof. Dependingon the condition of the subject, the therapeutic agent can be selectedfrom the group consisting of an antibiotic, e.g., vancomycin, amikacin,eftazidime, cefuroxime, moxifloxacin, or a steroid, e.g., triamcinolone,dexamethasone, and prednisolone. The presently disclosed particlecompositions can be administered prophylactically to prevent or reducethe occurrence of a post-operative infection of the anterior chamber orcan be administered therapeutically to treat an infection of theanterior chamber, e.g., endophthalmitis.

In some embodiments, the presently disclosed particle compositions canprovide an effective vehicle for sustained drug delivery directly to theretina. For example, the presently disclosed subject matter demonstratesthat 200-nm latex particles, coated with a representative coating suchas, for example poly(ethylene glycol) covalently bound to the particles,can be retained in the eyes of living rabbits for more than one monthwith no significant clearance and for over two months with only minimalclearance.

Further, the presently disclosed subject matter shows that uncoated200-nm latex particles caused substantial fibrin aggregation suggestiveof inflammation after intraocular injection in living rabbits. Also,uncoated 200-nm latex particles were found to cause visible vitreousopacities after intravitreal injection in living rabbits. By suitablymodifying size and/or surface chemistry, the presently disclosedparticle compositions can be engineered to avoid visual obstruction andinflammation in the vitreous chamber.

Other sustained release drug systems, when injected subconjunctivally,afford limited intraocular bioavailability of delivered medications dueto barriers to drug penetration. Further, free drugs, when injected intothe vitreous require multiple injections per year due to drug metabolismand clearance. In contrast, the presently disclosed particlecompositions, when injected into the vitreous, can be retained for longperiods of time.

In some embodiments, the presently disclosed subject matter includesmedications combined with particles, wherein the medications include,but are not limited to, anti-inflammatory drugs, antimicrobials,anti-angiogenesis agents, immunosuppressants, anti-neoplastic agentsand/or combinations thereof. Such combinations allow for the treatmentof conditions that require more than one medication.

More particularly, the presently disclosed subject matter includesparticle compositions containing anti-inflammatory agents for thetreatment and/or prevention of macular edema and/or other inflammatorydiseases of the retina. In some embodiments, the presently disclosedsubject matter includes particle compositions containing anti-neoplasticagents for treatment of intraocular cancers. In yet other embodiments,the presently disclosed subject matter includes particle compositionscontaining immunosuppressant agents for the treatment of autoimmuneand/or inflammatory diseases of the retina.

In other embodiments, the presently disclosed subject matter includesparticles coated with and/or otherwise carrying antibodies, wherein theantibodies are a therapeutic agent and can be released over time. In yetother embodiments, the presently disclosed subject matter includesparticles combining a therapeutic antibody coating with othertherapeutic agents, e.g., one or more medications.

The presently disclosed subject matter also includes pharmaceuticalformulations for intravitreal injection containing solutions of thepresently disclosed particle compositions containing and/or coated withanti-angiogenesis agents (antibodies) for use in degenerative diseasesof the retina and/or proliferative retinopathy and/or other vasculardiseases of the retina. Some representative embodiments includepharmaceutical formulations containing solutions of particlecompositions containing anti-inflammatory and/or antimicrobial agentsfor the prevention and/or treatment of post-surgical complicationsand/or infections after vitreoretinal operations. Further,pharmaceutical formulations containing solutions containingantibacterial and/or antifungal and/or anti-amoebic and/or antiviralagents for treatment of infectious processes of the vitreous and/orretina, including, but not limited to, endophthalmitis also aredisclosed. Combinations of the above-mentioned pharmaceuticalformulations also are contemplated by the presently disclosed subjectmatter.

For example, the presently disclosed subject matter provides a methodfor treating age-related macular degeneration in a subject in need oftreatment thereof, the method involving administering via intravitrealinjection to a vitreous chamber and/or retina of an eye of the subjectthe presently disclosed particle compositions containing one or moretherapeutic agents selected from the group consisting of anti-vascularendothelial growth factor (VEGF) agents, including, but not limited topegaptanib, bevacizumab, anecortane acetate, squalamine lactate,ranibizumab, or corticosteroids, including, but not limited to,triamcinolone acetonide.

In other embodiments, the presently disclosed subject matter provides amethod for treating proliferative diabetic retinopathy in a subject inneed of treatment thereof, the method involving administering viaintravitreal injection to a vitreous chamber and/or retina of an eye ofthe subject the presently disclosed particle compositions containing oneor more therapeutic agents selected from the group consisting ofsteroids, such as triamcinolone acetonide, ovine hyaluronidase, VEGFantibodies, such as bevacizumab, or VEGF antibody fragments, such asranibizumab, and combinations thereof.

In yet other embodiments, the presently disclosed subject matterprovides a method for treating ocular cancer in a subject in need oftreatment thereof, the method involving administering via intravitrealinjection to a vitreous chamber and/or retina of an eye of a subject thepresently disclosed particle compositions containing one or moreanti-neoplastic agents. Representative anti-neoplastic agent include,but are not limited to, fluoropyrimidine, pyrimidine nucleoside,platinum analogue, anthracycline, anthracenedione, epipodophyllotoxin,camptothecin, vinca alkaloid, and combinations thereof.

The particles according to the compositions and methods disclosed hereincan be of any size that is consistent with effective treatment of theeye disorders disclosed herein, in the judgment of a person of ordinaryskill in the art. For example, particles of any size can be usedprovided they do not obstruct the flow of intraocular fluids into and/orout of the eye compartment into which the particle composition isadministered, which could increase inflammation or IOP. Particles havinga diameter of, for example, from about 1 nm to about 100,000 nm, or fromabout 1 nm to about 50,000 mm or from about 50 nm to about 50,000 nm, orfrom about 1 nm to about 30,000 nm, or from about 1 nm to about 10,000nm, or from about 1 nm to about 1,000 nm, can be used according to thecompositions and methods disclosed herein. Particles having a diameterof for example, at least about 1 nm, at least about 10 nm, at leastabout 50 nm, at least about 100 nm, at least about 300 nm, at leastabout 300 nm or more can be used. Particles having a diameter of lessthan about 100,000 nm, or less than about 50,000 nm, or less than about25,000 nm, or less than about 10,000 nm, or less than about 6,000 nm, orless than about 5,000 nm, or less than about 2,000 nm, or less thanabout 1,000 nm, or less than about 800 nm, or less than about 600 nm, orless than about 500 nm, or less than about 200 nm can be used. Particlesof different diameters may be appropriate for administration todifferent eye compartments. For example, particles for intravitrealadministration can have a diameter of at least about 1 nm, or from about1 nm to about 50,000 nm, or any other diameter range disclosed hereto.Particles for administration into the anterior chamber can have adiameter of, for example, from about 1 nm to about 7,000 nm, or fromabout 10 nm to about 6,000 nm, or from about 100 nm to about 2,000 nm,or from about 600 to about 1000 nm; or less than about 6,000 nm, or lessthan about 2,000 nm, or less than about 1,000 nm, or less than about 800nm.

In some embodiments, the drug delivery system can include, for example,(i) a substrate; and (ii) a coating associated with the substrate. Asused herein, a “substrate” is any substance, device or apparatus thatcan be coated according to the compositions and methods disclosed hereinand thereafter administered to a patient. A substrate can be, forexample, a medical device or an implant, or a particle as describedherein. The substrate can be of any size that is consistent witheffective delivery of a therapeutic agent to a patient, in the judgmentof a person of ordinary skill in light of the compositions and methodsdisclosed herein. A substrate can have a diameter of, for example, atleast about 1 nm, or at least about 1 micron, or at least about 1 mm, orat least about 10 mm; or from about 1 nm to about 10 mm, or from about 1nm to about 1 mm, or from about 1 nm to about 100 microns, or from about1 nm to about 10 microns, or from about 1 nm to about 1 micron. Asubstrate can be, for example, suitable for administration to a patientby any means known in the art, for example by injection or other form ofsystemic administration, whether rectally, transmucosally, transnasally,intestinally, parenterally, intramuscularly, subcutaneously,intrameduallarily, intrathecally, intraventricularly, intravenously,intraperitoneally, intranasally, intraocularly, or transurethrally; ortopically; or via implantation into any region of the body of a patient.In some embodiments, the coating presents a hydrophilic region to theenvironment around the substrate. The drug delivery system can include,for example, a therapeutically effective amount of a therapeutic agent.The drug delivery system can, for example, bring about reducedinflammation when administered to the patient than if a drug deliverysystem comprising an uncoated particle were administered to the patient.As would be appreciated by a person of ordinary skill, the compositionsand methods disclosed herein can be applied to drug delivery systems ofany size range, up to and including of a size suitable for implants,including for example, intraocular implants, or the like.

The drug delivery system can also include, for example, (i) a substrate;(ii) a coating associated with the substrate, wherein the coatingpresents a hydrophilic region to the environment around the substrate;and (iii) a therapeutically effective amount of a therapeutic agent. Insome embodiments, the drug delivery system is suitable foradministration to a patient. The drug delivery system can, for example,bring about reduced inflammation when administered to the patient thanif a drug delivery system comprising an uncoated substrate wereadministered to the patient.

In some embodiments the particles of the compositions and methodsdisclosed herein are nanoparticles. As used herein, the term“nanoparticle” refers to a particle having at least one dimension in therange of about 1 nm to about 1000 nm, including any integer valuebetween 1 nm and 1000 nm (including about 1, 2, 5, 10, 20, 50, 60, 70,80, 90, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900 and 1000nm and all integers and fractional integers in between). In someembodiments, the nanoparticle has at least one dimension, e.g., adiameter, of about 100 nm. In some embodiments, the nanoparticle has adiameter of about 200 nm. In other embodiments, the nanoparticle has adiameter of about 500 nm. In yet other embodiments, the nanoparticle hasa diameter of about 1000 nm (1 μm). In such embodiments, the particlealso can be referred to as a “microparticle.” As used herein,“microparticle” refers to a particle having at least one dimension inthe range of about 1 μm to about 100 μm, including any integer valuebetween 1 μm and 100 μm (including about 1, 2, 3, 10, 20, 30 40, 50, 60,70, 80, 90 and 100 μm and all integers and fractional integers inbetween). Exemplary microparticles have a diameter of less than about100 microns, less than about 50 microns, less than about 10 microns,less than about 5 microns, or less than about 3 microns, or less thanabout 2 microns. The term “particle” as used herein is meant to includenanoparticles and microparticles.

It will be appreciated by one of ordinary skill in the art thatparticles suitable for use with the presently disclosed methods canexist in a variety of shapes, including, but not limited to, spheroids,rods, disks, pyramids, cubes, cylinders, nanohelixes, nanosprings,nanorings, rod-shaped particles, arrow-shaped particles, teardrop-shapedparticles, tetrapod-shaped particles, prism-shaped particles, and aplurality of other geometric and non-geometric shapes. In someembodiments, the presently disclosed particles have a spherical shape.

In some embodiments, the presently disclosed particles includepolystyrene particles. For example, the presently disclosed particlesinclude carboxyl-modified polystyrene particles. The presently disclosedparticles in some embodiments can be tagged, e.g., with a fluorescentmolecule, to enable them to be detected or monitored when administeredto a subject. For example, in some embodiments, the particles includeyellow-green fluorescent carboxyl-modified polystyrene particles(Molecular Probes, Eugene, Oreg.).

Further, in some embodiments, the presently disclosed particles can besurface modified, e.g., by covalently attaching PEG, often referred toas being PEGylated. Such particles can be prepared as disclosed in Laiet al., “Rapid transport of large polymeric nanoparticles in freshundiluted human mucus,” Proc. Natl. Acad. Sci. U.S.A., 104(5); 1482-1487(2007) and Suh et al., “PEGylation of nanoparticles improves theircytoplasmic transport,” Int. J. Nanomed., 2(4), 735-741 (2007).

For example, one 100- to 500-nm yellow-green fluorescent,carboxyl-modified polystyrene (PS) particles (Molecular Probes, Eugene,Oreg.) can be dialyzed extensively against PBS (300 kDa, Spectrum Lab,Rancho Dominguez, Calif.). Polyethylene glycol can be covalentlyattached to the particles via carboxyl-amino reaction. Briefly, diaminePEG (molecular mass>2,000 Da, e.g., 3,400 Da; Nektar Therapeutics, SanCarlos, Calif.) can be dissolved in 50 mM 2-(N-morpholino)ethanesulfonicacid (MES) buffer (Sigma, St. Louis, Mo.) at pH 6. PEG can be added todifferent sized nondialyzed particles to yield final concentrations of3:1. PEG:COOH and 1% solids/mL. After 15 minutes,1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (Sigma, St Louis, Mo.)can be added to a final concentration of 4 mg/mL, pH adjusted to 6.5,and incubated on an orbital shaker for 2 hours at room temperature. Toquench the reaction, glycine (J. T. Baker, Phillipsburg, N.J.) can beadded to a final concentration of 100 mM. The solution can be incubatedfor 30 minutes at room temperature and subsequently dialyzed extensivelyagainst PBS in a 300,000 kDa MWCO Float-a-lyzer (Spectrum Laboratories,Rancho Dominguez, Calif.). Unmodified particles were dialyzed similarlyto remove all traces of sodium azide originally added by themanufacturer.

Size and ζ-potential can be determined by dynamic light scattering andlaser Doppler anemometry, respectively, using, for example, a Zetasizer3000 (Malvern Instruments, Southborough, Mass.). Size measurements canbe performed, for example, at 25° C. at a scattering angle of 90°.Samples can be further diluted in double-distilled water.

Representative characteristics of particles prepared by the method ofLai et al. are summarized in Table 1.

TABLE 1 Representative Characteristics of COOH— and PEG-Modified PSParticles Nominal Surface Size (nm) Chemistry Diameter (nm) ξ-potential(mV) 100 COOH 109.2 ± 3.1 −41.0 ± 1.9 100 PEG 122.4 ± 5.2  −4.4 ± 1.1200 COOH 216.6 ± 4.5 −58.8 ± 4.2 200 PEG 232.3 ± 6.8  −2.1 ± 0.3 500COOH 515.0 ± 7.2 −61.0 ± 0.5 500 PEG 529.1 ± 8.1  −5.6 ± 0.4

In certain embodiments, the particles can be combined with an activeingredient, e.g., a drug, medication, or therapeutic agent. Activeingredients include, but are not limited to, any component, compound, orsmall molecule that can be used to bring about a desired effect, e.g., atherapeutic effect. For example, a desired effect can include thediagnosis, cure, mitigation, treatment, or prevention of a disease orcondition.

The active ingredient can be adsorbed, encapsulated, entangled,embedded, incorporated, bound to the surface, or otherwise associatedwith the particle. As used herein, “combined” encompasses adsorbed,encapsulated, associated, entangled, embedded, incorporated, bound tothe surface, or any other means for holding two substances or itemstogether. As provided hereinabove, in some embodiments the presentlydisclosed particles can include a functional group, e.g., a carboxylgroup. Other functional groups include, but are not limited to, asulhydryl, hydroxyl, and/or amino group. The functional groups can beavailable, for example, for drug binding (covalent or electrostatic) orfor other desired purposes within the scope of the presently disclosedsubject matter.

The subject treated by the presently disclosed methods in their manyembodiments is desirably a human subject, although it is to beunderstood that the methods described herein are effective with respectto all vertebrate species, which are intended to be included in the term“subject”. Accordingly, a “subject” can include a human subject formedical purposes, such as for the treatment of an existing condition ordisease or the prophylactic treatment for preventing the onset of acondition or disease, or an animal subject for medical, veterinarypurposes, or developmental purposes. Suitable animal subjects includemammals including, but not limited to, primates, e.g., humans, monkeys,apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines,e.g., sheep and the like; caprines, e.g., goats and the like; porcines,e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras,and the like; felines, including wild and domestic cats; canines,including dogs; lagomorphs, including rabbits, hares, and the like; androdents, including mice, rats, and the like. In some embodiments, thesubject is a human including, but not limited to, fetal, neonatal,infant, juvenile, and adult subjects. Further, a “subject” can include apatient afflicted with or suspected of being afflicted with a conditionor disease. Thus, the terms “subject” and “patient” are usedinterchangeably herein.

The terms “treat” or “treating,” and grammatical derivatives thereof, asused herein refer to any type of treatment that imparts a benefit to asubject afflicted with a disease or illness, including any measurableimprovement in the condition of the subject, reducing a symptom of thecondition, inhibiting an underlying cause or mechanism related to thecondition, delaying the progression of the condition, preventing ordelaying the onset of the disease or illness, e.g., prophylactictreatment, enhancing normal physiological functionality, and the like.Thus, treating does nor require a cure.

The term “effective,” as that term is used in the specification and/orclaims, means adequate to accomplish a desired, expected, or intendedresult. More particularly, a “therapeutically effective amount” asprovided herein refers to an amount of the presently disclosed particlecompositions necessary to provide the desired therapeutic effect, e.g.,an amount that is effective to prevent, alleviate, ameliorate orotherwise treat symptoms of disease or prolong the survival of thesubject being treated. As would be appreciated by one of ordinary skillin the art upon review of the present disclosure and as provided in moredetail herein below, the exact amount required will vary from subject tosubject, depending on age, general condition of the subject, theseverity of the condition being treated, the particular compound and/orcomposition administered, and the like. An appropriate “therapeuticallyeffective amount” in any individual case can be determined by one ofordinary skill in the art by reference to the pertinent texts andliterature and/or by using routine experimentation.

The presently disclosed particle compositions can be administeredtherapeutically to achieve a therapeutic benefit or prophylactically toachieve a prophylactic benefit. By therapeutic benefit is meant treatingthe underlying disorder including eradication or amelioration of one ormore of the symptoms associated with the underlying disorder such thatthe patient reports an improvement in feeling or condition,notwithstanding that the patient can still be afflicted with theunderlying disorder. For example, administration of a particlecomposition to a patient suffering from a condition provides therapeuticbenefit not only when the underlying condition is eradicated orameliorated, but also when the patient reports a decrease in theseverity or duration of the symptoms associated with the condition.Therapeutic benefit also includes halting or slowing the progression ofthe disease, regardless of whether improvement is realized by thepatient.

For prophylactic administration, the presently disclosed particlecompositions can be administered to a subject at risk of developing aparticular ocular condition or disorder. Alternatively, prophylacticadministration can be applied to avoid the onset of symptoms in apatient diagnosed with the underlying condition or disorder.

The amount of the presently disclosed particle compositions administeredto a subject will depend upon a variety of factors, including, forexample, the particular indication being treated, the mode ofadministration, whether the desired benefit is prophylactic ortherapeutic, the severity of the indication being treated and the ageand weight of the patient, the bioavailability of the particular activecompound, and the like. Determination of an effective dosage is wellwithin the capabilities of those skilled in the art.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC50 of the particular therapeutic agent asmeasured in an in vitro assay known in the art. Calculating dosages toachieve such circulating blood or serum concentrations taking intoaccount the bioavailability of the particular compound is well withinthe capabilities of skilled artisans. For guidance, see Fingl &Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein.

Initial dosages also can be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of therapeuticagents to treat or prevent the various diseases described above arewell-known in the art. Dosage amounts will depend on, among otherfactors, the activity of the therapeutic agent, its bioavailability, themode of administration and various factors discussed above. Dosageamount and interval can be adjusted individually to provide levels ofthe therapeutic agents(s) sufficient to maintain a therapeutic orprophylactic effect. Skilled artisans will be able to optimize effectivelocal dosages without undue experimentation.

The presently disclosed particle compositions can be administered onceper day, a few or several times per day, or even multiple times per day,depending upon, among other things, the indication being treated and thejudgment of the prescribing physician.

Preferably, the presently disclosed particle compositions will providetherapeutic or prophylactic benefit without causing substantialtoxicity. Toxicity of the particle compositions can be determined usingstandard pharmaceutical procedures. The dose ratio between toxic andtherapeutic (or prophylactic) effect is the therapeutic index.Compositions that exhibit high therapeutic indices are preferred.

As provided hereinabove, the presently disclosed particles, inparticular embodiments, will contain one or more “active compounds” or“therapeutic agents.” Pharmaceutical compositions containing thepresently disclosed particle compositions also are provided herein.These pharmaceutical compositions include the presently disclosed activecompounds in a pharmaceutically acceptable carrier. The term“pharmaceutically acceptable” with respect to a component, such as asalt, carrier, excipient or diluent of a composition according to thepresently disclosed subject matter refers to a component that iscompatible with the other ingredients of the composition in that it canbe combined with the presently disclosed particle compositions withouteliminating the therapeutic efficacy of the active compounds ortherapeutic agents and is suitable for use with subjects as providedherein without undue adverse side effects (including, but not limitedto, toxicity, irritation, and allergic response) to the subject to whichthe particular particle composition is administered. Examples ofpharmaceutical acceptable components include, without limitation, any ofthe standard pharmaceutical carriers, such as phosphate buffered salinesolutions, water, emulsions such as oil/water emulsion, microemulsions,and various types of wetting agents.

When used to treat or prevent conditions and diseases as describedherein, the presently disclosed active compounds can be administeredsingly, as mixtures of one or more active compounds or in mixture orcombination with other agents useful for treating such diseases and/orthe symptoms associated with such diseases.

Further, in representative embodiments, certain active compounds and/ortherapeutic agents disclosed herein are prodrugs. The term “prodrug”refers to a therapeutic agent that has been chemically derivatized suchthat, upon administration to a subject, the derivative is metabolized toyield the biologically-active therapeutic agent. Accordingly, uponadministration to a recipient, a prodrug is capable of providing(directly or indirectly) a compound of the presently disclosed subjectmatter or an inhibitorily active metabolite or residue thereof. Prodrugscan increase the bioavailability of the presently disclosed compoundswhen such compounds are administered to a subject (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or can enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to ametabolite species.

Pharmaceutical compositions containing the presently disclosed particlecompositions, including active compounds (or prodrugs thereof), can bemanufactured by means of conventional mixing, dissolving, granulating,dragee-making levigating, emulsifying, encapsulating, entrapping and/orlyophilization processes. The presently disclosed pharmaceuticalcompositions can be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliariesthat facilitate processing of the active compounds into preparationsthat can be used pharmaceutically.

Useful injectable compositions containing the presently disclosedparticle compositions include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions also can contain formulating agents, such as suspending,stabilizing and/or dispersing agents. The compositions suitable forinjection can be presented in unit dosage form, e.g., in ampules or inmultidose containers, and can contain added preservatives.Alternatively, an injectable composition can be provided in powder formfor reconstitution with a suitable vehicle, including, but not limitedto, sterile water, buffer, dextrose solution, and the like, before use.To this end, the presently disclose particles can be dried by anyart-known technique, such as lyophilization, and reconstituted prior touse.

In addition to the presently disclosed particle compositions, thepharmaceutical formulations can contain other additives, such aspH-adjusting additives. In particular, useful pH-adjusting agentsinclude acids, such as hydrochloric acid, bases or buffers, such assodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodiumborate, or sodium gluconate. Further, the formulations can containanti-microbial preservatives. Useful, anti-microbial preservativesinclude methylparaben, propylparaben, and benzyl alcohol. Theanti-microbial preservative is typically employed when the formulationis placed in a vial designed for multi-dose use.

EXAMPLES

The presently disclosed subject matter now will be described more fullyhereinafter with reference to the accompanying Examples, in which some,but not all embodiments of the inventions are shown. The followingExamples have been included to provide guidance to one of ordinary skillin the art for practicing representative embodiments of the presentlydisclosed subject matter. In light of the present disclosure and thegeneral level of skill in the art, those of skill can appreciate thatthe following Examples are intended to be exemplary only and thatnumerous changes, modifications, and alterations can be employed withoutdeparting from the scope of the presently disclosed subject matter. Thefollowing Examples are offered by way of illustration and not by way oflimitation.

Example 1 Preparation and Characterization of PEG-Coated Particles

Fluorescent, carboxyl-modified polystyrene particles (Molecular Probes,Eugene, Oreg.) were covalently modified with 2-3.4 kDa amine-modifiedPEG (Nektar Therapeutics, San Carlos, Calif.) via a carboxyl-aminereaction, as previously published. Unconjugated PEG was removed by threerounds of washing and centrifugation. The PEG-coated particles werestored at 4° C. until use. A near-neutral ζ-potential measured byDoppler anemometry was used to confirm PEG conjugation. These particlesare also referred to herein as coated latex particles.

Example 2 Particle Administration to the Corneal Stroma

Particles according to Example 1 were administered to the corneal stromain one of two ways depending on the most appropriate dose for a clinicalsituation. Direct intrastromal injections were used to provide smallervolumes of particle solution to the cornea. Such injections involvedinsertion of a small gauge needle into the stromal layer of the cornea.These injection sites are most often self sealing. They can, however, beclosed with the aid of corneal glue and/or contact lens placement ifleakage occurs.

Larger doses of particles were administered by first creating a pocketin the corneal stroma. The pocket was created outside the visual axisand the size was determined based on the required dose. The particleswere then administered directly into the pocket, which was then closedwith corneal glue and placement of a contact lens for the firstpost-operative day.

Example 3 Particle Administration to the Anterior Chamber

Intraoperative Injection

Small incisions are created in the cornea during cataract extractionsurgery. These incisions, which are used for removing the cataractouslens and implanting the artificial lens, are closed by a process ofhydrosealing at the end of surgery. The particles are injected into theAC through the surgical incision and sealed in the chamber once thewound is closed.

Non-Operative Administration

A small gauge needle was inserted through the peripheral cornea and usedto inject the solution of particles according to Example 1 into the AC.These injection sites are most commonly self-sealing, however, cornealglue and/or contact lens placement were used for the first 24 hours toprevent leakage.

Example 4 Particle Administration into the Vitreous Chamber

Injections of particle solutions into the vitreous chamber wereperformed through the pars plana, an anatomic location that is devoid ofvasculature and retinal tissue, limiting the risk of bleeding andretinal and/or lens injury. A small gauge needle was used to injectparticles according to Example 1. Injection sites of this size are selfsealing, eliminating the need for closure. Injections were performedafter first disinfecting and topically anesthetizing the site.

Example 5 Sustained and Targeted Drug Delivery with IntrasomalMicroparticles and Nanoparticles for Treating Chronic Keratitis andCorneal Graft Rejection

Purpose

Many cases of amoebic and fungal keratitis, as well as corneal graftrejection, remain refractory to topical therapy. Intrastromal (IS)injection of medications has been introduced as an alternative totopical administration, but IS injection remains limited due to drugloss by diffusion and clearance. The presently disclosed subject matterdemonstrates that IS administration of micro- and nanoparticles snob aslatex particles can be used for sustained delivery of antimicrobials orimmunosuppressant agents to the cornea.

Methods

This embodiment included studying three groups, each with three rabbits.The three groups included: (a) a control group receiving 10 μL of salineinto an intrastromal pocket; (b) a microparticle group receiving 10 μLof 1-μm particles covalently coated with PEG in the pocket; and (c) ananoparticle group receiving 10 μL of 200-nm particles covalently coatedwith PEG into the pocket.

The retention of the particles was assessed by in vivo fluorescence. Theimages were obtained at zero (0) minutes; one hour; six hours; daily forone week; and every other day for fourteen days. The initialfluorescence value for each eye was used to determine the relativeclearance of particles from the corneal stroma.

Results

Micro- and nanoparticles were cleared from the stroma at similar rates(P<0.05). At one hour, a clearance of 21% of the 1-μm particles and 23%of the 200-nm particles was observed. At 24 hours, a loss of 52% and 41%of the total injection 1-μm particles and 200-nm particles,respectively, was observed. The rate of clearance became more gradualwith time: at 14 days, 79% and 73% of the original dose of the 1-μmparticles and 200-nm particles were lost, respectively. The controlgroup had no detectable fluorescence at any time point.

Conclusion

The observation that more than 20% of the presently disclosed particlesare still present in the corneal stroma after 14 days indicates that ISmicro- and nanoparticles provide a method for long-term delivery ofmedications to the cornea and could be useful in the management andtreatment of chronic keratitis and graft rejection.

Example 6 Intracameral Injection of Particles for Sustained Delivery ofPost-Operative Medications to the Anterior Chamber

Purpose

Intracameral (IC) administration of antimicrobial and anti-inflammatoryagents during intraocular surgery has been proposed to decrease the needfor post-operative topical drop. Free drugs, however, are cleared withthe aqueous humor (AH). The presently disclosed subject matterdemonstrates the use of particles for longer-term delivery ofmedications to the anterior chamber (AC), by evaluating the clearancerates and complications associated with the administration of ICparticles.

Methods

Nine rabbit eyes were examined in this embodiment. Baseline fluorescenceand intraocular pressures (IOP) were assessed. Groups included: (a)control—100 μL of IC saline; (b) uncoated—100 μL of IC 200-nm uncoatedlatex particles; and (c) coated—100 μL of IC 200-nm latex particle,which were coated with PEG. The particles were linked to fluorescencetags, which allowed detection by in vivo fluorescence. Fluorescenceimages and IOP measurements were obtained at zero (0) minutes; one hour;six hours; daily for one week; and every two days for one month.Relative particle retention was evaluated by comparing fluorescenceimages to those obtained a t=0.

Results

No fluorescence was detected in the control group. Particle loss wasobserved immediately after injection in both experimental groups:Significant percentages of both the coated and uncoated particlesremained after one day and 15 days. After 30 days, 33% and 18% of thetotal particles were retained in the coated and uncoated groups,respectively. A significantly greater clearance of uncoated particles(P<0.05) was observed. Only one animal, from the uncoated group,developed elevated IOP after the injection, which resolved progressivelywithin 16 days.

Conclusion

The presently disclosed, subject matter demonstrates that intraoperativeIC Injection of particles of nano-size or larger can be a useful toolfor providing sustained delivery of post-operative medications to the ACfor as long as one month.

Example 7 Intravitreal Particles for the Sustained Treatment ofDegenerative and Proliferative Diseases of the Retina

Purpose

Intravitreal injection of angiogenesis inhibitors has become commonplacein the treatment of retinal diseases, such as age-related maculardegeneration and proliferative diabetic retinopathy. Unfortunately, thisroute of delivery requires repeated injections, increasing the risk ofinfection and retinal injury. The presently disclosed subject matterdetermines the length of time particles can be retained in the vitreouschamber after pars plana injection and demonstrates the use of thepresently disclosed drug carriers for the long-term treatment ofdiseases of a retina.

Methods

The study was conducted on nine rabbit eyes and included three groups:(a) a control group received a 100-μL intravitreal injection of saline;(b) an uncoated group received 100 μL of intravitreal 200-nm uncoatedlatex particle solution; and c) a coated group received 100 μL ofintravitreal 200-nm latex particles coated with PEG. The baselinefluorescence and intraocular pressure (IOP) were assessed prior toinjection through the pars plana. The particles were fluorescence taggedand assessment of retention was made by analysis of in vivo fluorescenceimaging. Images and IOP measurements were obtained at zero (0) minutes,one hour, daily for one week, and every five days for one month. Thefluorescence images from each time point were compared to those obtainedimmediately after the intravitreal infection to determine the relativeretention rates for each eye.

Results

No significant differences between the clearance profiles of the coatedand uncoated particles were observed. No significant decline in theparticles retained in the vitreous chambers was observed over 30 days(P<0.05). No detectable fluorescence signal was observed in the controlgroup. No changes in IOP were observed in any group.

Conclusion

The presently disclosed particles provide sustained and predictablerelease of medications and can be an effective system for long-termintravitreal drug delivery and the treatment of various retinaldiseases.

Example 8 Inflammation Profile Following Intracameral Injection ofParticles

Materials and Methods

Particle Synthesis

Fluorescent carboxyl-modified polystyrene particles 100-1000 nm in size(Molecular Probes, Eugene, Oreg.) were covalently conjugated with 2 kDadiamine PEG, according to methods known in the art.

PLGA (15 kDa) was fluorescently labeled with Alexa Fluor 647 cadaverine(AF647; Invitrogen Corporation, Carlsbad, Calif.) using a modifiedmethod, as previously described. Fluorescently labeled nanoparticleswere formed by emulsion method. To form the emulsion, 100 mg ofPLGA-AF647 dissolved in one ml of dichloromethane (DCM) was homogenizedat 10 k rpm for 2 min in 15 ml of aqueous phase (2% PVA, 10% F127, or10% F68), then added to 100 ml aqueous phase (0.1% PVA, 1% F127, or 1%F68) and stirred for 2 h to remove solvent. Particles were collected,washed twice, and resuspended.

Size and zeta-potential were determined by dynamic fight scattering andlaser Doppler anemometry, respectively, using a Zetasizer Nano ZS90(Malvern Instruments).

Groups and Numbers

This study included 30 eyes from 30 New Zealand white rabbits. Therewere 5 experimental groups and one control group, each with n=5 animals.Two experimental groups received intracameral (IC) injections ofpolystyrene (PS) particles; uncoated (PS-COOH) and coated withpoly(ethylene) glycol (PS-PEG). Three groups received IC injections ofbiodegradable poly(lactic-co-glycolic acid, PLGA); one group had nopluronics coating (PLGA-PVA), another with moderate pluronics coating(PLGA-F68) and another with dense pluronics coating (PLGA-F127). Thecontrol group received a sham IC injection with phosphate bufferedsaline (PBS).

Pre-Injection Assessment

The intraocular pressure (IOP) and anterior chamber (AC) inflammationwere evaluated in all animals to establish baseline levels beforeparticle suspension injection. Animals with elevated IOP or any signs ofinflammation were excluded from the study. The animals were anesthetizedwith an intramuscular injection (IM) of ketamine/xylazine solution. Oncegeneral anesthesia was achieved a drop of 0.5% proparacaine topicalanesthetic solution was instilled onto the surface of the right eye ofthe animal and a wire eyelid speculum was placed to keep the lid open.

A Reichert Tono-Pen contact tonometer was used to assess the IOP; fivemeasurements were obtained for each animal at each time point. Aslit-lamp biomicroscope exam was then performed to examine the AC forsigns of inflammation; criteria included presence of cells, flare andfibrin.

Injection Preparation

Injections were performed immediately after the particles weresynthesized. The suspension was homogenized using a table-top lab vortexand doses of 120 μL were measured and pipetted into individualmicrocentrifuge tubes. The particle suspensions were vortexed againimmediately prior to drawing them into the administration syringes. Inorder to ensure that none of the particle suspension was lost in thedeadspace of the syringe/needle during injection, an air cushion wascreated between the plunger and the particle suspension by first drawingair into the syringe prior to the suspension.

Particle Injection

The animals were anesthetized as outlined above. Once general anesthesiawas achieved, a drop of 0.5% proparacaine was instilled onto the righteye of the animal prior to placement of a wire eye lid speculum. A 30gauge needle attached to an empty 1 cc Luer-lock syringe was insertedinto the AC through the peripheral cornea using a narrow angle ofapproach, and 120 μL of aqueous humor (AH) was extracted. While holdingthe needle in the place in the AC, the extraction syringe was detachedand the syringe containing the particle suspension (or control PBS) wasattached to the needle and the contents were infected into the AC. Theneedle and syringe were quickly withdrawn and a drop of cyanoacrylatecorneal glue was immediately placed on the injection site. The animalswere monitored until anesthesia reversal, at which time they werereturned to their cages.

Post-Injection Assessment

The animals were evaluated on post-injection days 1, 7, 14 and 30 andthe same evaluation procedure was performed on each day. After generaland local anesthesia were achieved, each animal was examined for grossabnormalities. IOP was measured as indicated above. Slit-lampbiomicroscopy was performed to evaluate and quantity AC inflammation.The exams were performed by the same trained ophthalmologist who wasblinded to the assignment of the treatment and control animals. The ACinflammation was quantified using a modified version of the StandardUveitis Nomenclature clinical grading scheme, as detailed below.

Modified Standardization of Uveitis Nomenclature (SUN) Scheme Part 1.Grading Scheme for Anterior Chamber Cells Grade Cells in Field 0 <1   0.5 1-5 1  6-15 2 16-25 3 26-50 4 >50 Part 2. Grading Scheme forAnterior Chamber Flare Grade Description 0 None 1 Faint 2 Moderate (irisand lens details clear) 3 Marked (iris and lens details hazy) 4 Intense(fibrin or plastic aqueous) Part 3. Grading Scheme for Anterior ChamberFibrin Reaction Grade Fibrin Morphology 0 None 1 Spots, non-continuous 2Lines or semi-transparent membranes 3 Flat opaque patches 4 IsometricmassesResults

The mean inflammation scores for each group are presented below in Table1 as well as in FIG. 1. At day 1 there was clinically visible ACinflammation is all animals in all groups, including the control group.The inflammation trend was similar for all groups: a rapid rise from thetime of injection with a peak score at Day 1, followed by a progressivedecline until the end of the study (Day 30).

The inflammation was significantly higher in the PS-COOH, PLGA-PVA, andPLGA-F68 groups compared to the PS-PEG, PLGA-F127 and Saline groups atall time points. There was no significant difference among the scores ofPS-COOH, PLGA-PVA and PLGA-F68 groups (at any time point), and likewisethere was no significant difference among the scores of the PS-PEG,PLGA-F127 and Saline (Control) groups at any time point (P<0.05).

TABLE 1 The mean AC inflammation scores from among the animals (n = 5)in each group for each time point evaluated in this study. PostInjection Day Particle Day 0 Day 1 Day 7 Day 14 Day 30 PS-COOH 0 6.8 4.23.8 3.2 PS-PEG 0 5.4 2.8 1.8 1.2 PLGA-PVA 0 8.6 5 4.2 3.6 PLGA-F68 0 7.84.4 3.8 3.4 PLGA-F127 0 5.6 2.8 2 1.4 Gontrol 0 5.2 2.2 1.8 1.1

Although the foregoing subject matter has been described in some detailby way of illustration and example for purposes of clarity ofunderstanding, it will be understood by those skilled in the art thatcertain changes and modifications can be made without departing from thespirit and scope of the invention.

All publications, patent applications, patents, and other references areherein incorporated by reference to the same extent as if eachpublication, patent application, patent, and other reference wasspecifically and individually indicated to be incorporated by reference.It will be understood that, although a number of patent applications,patents, and other references are referred to herein, such referencedoes not constitute an admission that any of these documents forms partof the common general knowledge in the art.

REFERENCES

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The invention claimed is:
 1. A method for treating an eye disease ordisorder in a patient in need thereof, comprising administering to apart of the eye of the patient, a drug delivery system comprising:particles having a diameter between 30 nm and 50 microns, the particlescomprising a biocompatible polymeric core comprising a blend of polymersselected from the group consisting of polylactic acid,poly(lactide-co-glycolide), polyglycolic acid, and copolymers thereof; acoating of polyalkylene oxide polymer or copolymer, wherein at leastabout 10%, at least about 25%, at least about 50%, at least about 75%,at least about 90%, at least about 95%, or at least about 99% of thepolyalkylene oxide polymer or copolymer are amphiphilic copolymers orblock copolymers comprising hydrophobic segments with molecular weightsof at least about 1.8 kDa, at least about 2 kDa, at least about 2.5 kDa,at least about 3 kDa, at least about 3.5 kDa, at least about 4.0 kDa, atleast about 4.5 kDa, or at least about 5.0 kDa or more, covalently ornon-covalently associated with the particle, therapeutic agent to treatan eye disease or disorder; wherein the drug delivery system providessustained release of the therapeutic agent into the vitreous chamberover a period of time of at least three months, and wherein the vitreouschamber of the eye exhibits at least 10% less inflammation orintraocular pressure than if the particle were uncoated for at leastabout 30 days post-administration.
 2. The method of claim 1, wherein thecoating reduces the inflammation or intraocular pressure (IOP) elicitedby the uncoated particle by at least about 10%, 30%, or 50%, in thevitreous chamber of the eye for at least about 30 dayspost-administration.
 3. The method of claim 1, wherein at least about50% of the polymer in the hydrophobic regions of the amphiphiliccopolymer in the coating has a molecular mass of least about 2 kDa. 4.The method of claim 1, wherein the particles have a diameter betweenabout 1 micron and about 30 microns.
 5. The method of claim 1, whereinthe coating is bound covalently to the particles.
 6. The method of claim1, wherein the coating is non-covalently associated with the particles.7. The method of claim 1, wherein the eye disease or disorder isselected from the group consisting of amoebic keratitis, fungalkeratitis, bacterial keratitis, viral keratitis, onchorcercal keratitis,bacterial keratoconjunctivitis, viral keratoconjunctivitis, cornealdystrophic diseases, Fuchs' endothelial dystrophy, Sjogren's syndrome,Stevens-Johnson syndrome, an autoimmune dry eye disease, anenvironmental dry eye disease, a corneal neovascularization disease,post-corneal transplant rejection prophylaxis, post-corneal transplantrejection treatment, autoimmune uveitis, infectious uveitis, anterioruveitis, posterior uveitis, pan-uveitis, an inflammatory disease of theretina, an inflammatory disease of the vitreous, endophthalmitisprophylaxis, endophthalmitis treatment, macular edema, maculardegeneration, proliferative diabetic retinopathy, non-proliferativediabetic retinopathy, hypertensive retinopathy, age related maculardegeneration, an autoimmune disease of the retina, primary intraocularmelanoma, metastatic intraocular melanoma, an intraocular metastatictumor, open angle glaucoma, closed angle glaucoma, pigmentary glaucomaand combinations thereof.
 8. The method of claim 1 comprising injectingthe drug delivery system into an eye compartment selected from the groupconsisting of the vitreous chamber, the sclera, the stroma and theanterior chamber.
 9. The method of claim 1, wherein the therapeuticagent is selected from the group consisting of an anti-inflammatorydrug, an antimicrobial agent, an anti-angiogenesis agent, animmunosuppressant, a steroid, a chemotherapeutic agent, an ocularanti-hypertensive drug, and combinations thereof.
 10. The method ofclaim 1, wherein the drug delivery system provides sustained release ofthe therapeutic agent over a period of time of at least about 1 day, 1week, or 4 weeks.
 11. A drug delivery system comprising: particleshaving a diameter between 30 nm and 50 microns, the particles comprisinga biocompatible polymeric core comprising a blend of polymers selectedfrom the group consisting of polylactic acid,poly(lactide-co-glycolide), polyglycolic acid, and copolymers thereof; acoating of polyalkylene oxide polymer or copolymer, covalently ornon-covalently associated with the particle, wherein at least about 10%,at least about 25%, at least about 50%, at least about 75%, at leastabout 90%, at least about 95%, or at least about 99% of the polyalkyleneoxide polymer or copolymer are amphiphilic copolymers or blockcopolymers comprising hydrophobic segments with molecular weights of atleast about 1.8 kDa, at least about 2 kDa, at least about 2.5 kDa, atleast about 3 kDa, at least about 3.5 kDa, at least about 4.0 kDa, atleast about 4.5 kDa, or at least about 5.0 kDa or more, wherein thecoating is covalently or non-covalently associated with the surface ofthe particle; and a therapeutically effective amount of a therapeuticagent for treatment of an eye disease or disorder, wherein the drugdelivery system provides sustained release of the therapeutic agent intothe vitreous chamber of the eye of the patient over a period of time ofat least three months and wherein the vitreous chamber of the eyeexhibits at least 10% less inflammation or intraocular pressure than ifthe particle were uncoated for at least about 30 dayspost-administration.
 12. The method of claim 1, wherein the polymercoating comprises polyethylene glycol on a core ofpolylactide-co-glycolide, for delivery of a drug lowering intraocularpressure (IOP) or a steroidal anti-inflammatory.
 13. The drug deliverysystem of claim 11, wherein the particles are retained within an eyecompartment for periods of time greater than those observed withfree-standing drugs or uncoated particle compositions.
 14. The drugdelivery system of claim 11, wherein the polymer comprises hydrophobicsegments with molecular weights of at least about 4.0 kDa, at leastabout 4.5 kDa, or at least about 5.0 kDa or more.
 15. The drug deliverysystem of claim 11, wherein at least about 75%, at least about 90%, atleast about 95%, or at least about 99% of the hydrophobic regions inthese coatings have molecular weights of at least about 1.8 kDa.
 16. Thedrug delivery system of claim 11, wherein the therapeutic agent is ananti-angiogenic agent.
 17. The drug delivery system of claim 16, whereinthe anti-angiogenic agent is an anti-vascular epithelial growth factor(VEGF) agent.
 18. The drug delivery system of claim 11, wherein thetherapeutic agent is selected from the group consisting of timolol,betaxolol, bromonidine, and dorzolamide.
 19. The drug delivery system ofclaim 11, wherein the particles are between one and 30 microns indiameter.
 20. The drug delivery system of claim 11, wherein theparticles are between one and 50 microns in diameter.
 21. The drugdelivery system of claim 11, wherein the particles provide sustainedrelease of the therapeutic agent into the vitreous chamber of the eye ofthe patient over a period of time of at least six months.
 22. The drugdelivery system of claim 21, wherein the patient is a human.
 23. Thedrug delivery system of claim 11, wherein the particles are suspended ina sterile injectable composition.
 24. The drug delivery system of claim23, wherein the particles are lyophilized and reconstituted prior toadministration.
 25. The drug delivery system of claim 11, wherein thebiocompatible core comprises a blend of polylactic acid andpoly(lactide-co-glycolide).
 26. The drug delivery system of claim 25,wherein the therapeutic agent is an anti-angiogenic agent.
 27. The drugdelivery system of claim 26, wherein the therapeutic agent is ananti-vascular epithelial growth factor (VEGF) agent.
 28. The drugdelivery system of claim 27, wherein the particles are between one and30 microns in diameter.